Mutations

APP V604M

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP3, BS1, BS2
Clinical Phenotype: Alzheimer's Disease, Progressive Nonfluent Aphasia
Position: (GRCh38/hg38):Chr21:25911840 G>A
Position: (GRCh37/hg19):Chr21:27284152 G>A
dbSNP ID: rs199887707
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to ATG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 14

Findings

This variant was first identified in a Thai patient clinically diagnosed with probable early onset Alzheimer’s disease at age 55 (Van Giau et al., 2018). At that time, he displayed impairments in memory, object naming, verbal fluency, and executive function. MRI showed atrophy of the frontoparietal cortex and hippocampus. However, measurements of cerebrospinal fluid biomarkers Aβ42, total tau, and phospho-tau did not bolster the AD diagnosis, as none of the three biomarkers met prespecified cut-offs. (It should be noted that two years prior to receiving an AD diagnosis, the patient’s clinical symptoms were described as characteristic of progressive nonfluent aphasia.)

In addition to APP V604M, this patient carries 22 other missense variants in genes associated with AD or other dementias, including ABCA7, CR1, LRRK2, PINK1, PRNP, and SORL1. No likely pathogenic mutations were found in PSEN1, PSEN2, MAPT, or GRN.

The carrier’s father, uncle, and cousin developed memory problems in their sixth and seventh decades. Genetic information was not available from these or other family members, so it is unknown whether any of the variants identified in the proband segregates with disease.

The variant was also found in a control subject in a study of 1154 Alzheimer’s disease (AD) patients and 2403 controls of Chinese ancestry (Xiao et al., 2022).

V604M is found with an allele frequency of 4.596 X10-4 in the gnomAD database (v2.1.1, searched 2020-10-15) and 1.997 X10-4 in the 1000 Genomes Project database (Phase 3, searched 2020-10-15).

Biological Effect

The biological effect of the valine-to-methionine substitution has not been tested directly. The variant was predicted to be possibly damaging by PolyPhen-2, tolerated by SIFT, and neutral by PROVEAN (Van Giau et al., 2018). Its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD, Oct 2021).

Pathogenicity

Alzheimer's Disease : Benign

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  V604M: Most carriers are of European descent.

BS2-S

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 10 Jan 2023

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References

Paper Citations

  1. Van Giau V, Senanarong V, Bagyinszky E, Limwongse C, An SS, Kim S. Identification of a novel mutation in APP gene in a Thai subject with early-onset Alzheimer's disease. Neuropsychiatr Dis Treat. 2018;14:3015-3023. Epub 2018 Nov 8 PubMed.
  2. Xiao X, Liu H, Zhou L, Liu X, Xu T, Zhu Y, Yang Q, Hao X, Liu Y, Zhang W, Zhou Y, Wang J, Li J, Jiao B, Shen L, Liao X. The associations of APP, PSEN1, and PSEN2 genes with Alzheimer's disease: A large case-control study in Chinese population. CNS Neurosci Ther. 2023 Jan;29(1):122-128. Epub 2022 Oct 10 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Van Giau V, Senanarong V, Bagyinszky E, Limwongse C, An SS, Kim S. Identification of a novel mutation in APP gene in a Thai subject with early-onset Alzheimer's disease. Neuropsychiatr Dis Treat. 2018;14:3015-3023. Epub 2018 Nov 8 PubMed.

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